This program project focuses on the pathogenesis of Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) as models for understanding the interplay of genetic, neurobiological, and psychological factors during the course of CNS development. TS, OCD, and related conditions are prevalent disorders affecting as many as 0.3-3% of the population. They are frequently chronic and associated with marked impairment and disability. Although clinical care has improved over the past decade, a significant number of patients fail to respond adequately or experience intolerable side effects. The etiology of these disorders is unknown. Compelling evidence suggests that the vulnerability to develop TS and OCD is mediated by both genetic and environmental factors, and that neural systems located in the basal ganglia and functionally related brain structures are involved in their pathogenesis. Based on explicit models of pathogenesis for TS and OCD and building on work accomplished over the past six years, an array of clinical, neuropsychological, genetic, neuroimaging, epidemiological, neurobiological, and treatment studies are proposed. Translational and integrative studies of perinatal and immunological risk factors are of particular significance. If confirmed as being causally related to TS and OCD, they may lead to clinical and public health interventions, as well as the development of valid animal models. A multidisciplinary team of investigators has joined forces to test specific hypotheses through the integration and translation of basic and clinical neuroscience research. All subjects will be studied using identical clinical, neuropsychological, genetic, and neurobiological techniques. These studies are divided into seven projects and are supported by three cores.